Neoadjuvant Chemo-hypoRT Plus PD-1 Antibody (Tislelizumab) in Resectable LA-G/GEJ (RARE)

Neoadjuvant Chemo-hypofractionated Radiotherapy Plus PD-1 Antibody (Tislelizumab) in Locally Advanced Resectable Gastric or Gastroesophageal Junction Adenocarcinoma

Gastric cancer is the third leading cause of death due to cancer worldwide. Although the consensus on the surgical treatment has resulted in the improvement of curative effect during the past decades, controversies remained for the perioperative therapy of gastric cancer, especially in the selection of the optimal neoadjuvant regimens. Immunotherapy with anti-programmed cell death-1 (PD-1) antibody has demonstrated moderate efficacy in selected patients with advanced gastric adenocarcinoma. Hypofractionated radiotherapy (HypoRT) may act synergistically with immunotherapy to enhance antitumor responses. This phase II trial study want to exploit the efficacy and safety to give PD-1 antibody (Tislelizumab) with combination chemotherapy and HypoRT before surgery in treating adult patients with gastric or gastroesophageal junction adenocarcinoma.

Study Overview

• Status: Completed
• Conditions: Gastric or Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Combination product: neoadjuvant chemo-hypofractionated radiotherapy plus PD-1 antibody (Tislelizumab)

Detailed Description

1. This clinical trial will be conducted under Simon's optimal two-stage design. The first stage needs 9 participants, if ≥1 participants acquire remission, then the study will move on to the second stage and enroll the rest 10 participants. Taking into account a drop-out rate of about 5%, we planned to enroll 21 patients.
2. Target population: patients with resectable locally advanced resectable gastric or gastroesophageal junction adenocarcinoma (cT1-2N+M0/T3-T4aNanyM0).
3. Trial design: This is a monocenter, single arm, phase II study to evaluate the efficacy and safety of neoadjuvant chemo-hypofractionated radiotherapy plus PD-1 antibody (Tislelizumab) in patients with locally advanced gastric or gastroesophageal junction adenocarcinoma.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Jiangsu Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma involving the gastroesophageal junction or gastric cardia.
2. Having an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 7 days before enrollment.
3. Being histologically diagnosed with adenocarcinoma.
4. Having tumor lesions at stomach or gastroesophageal junction (Siewert type II or III);
5. Clinically diagnosed stage T1-2N+M0/T3-T4aNanyM0 according to ultrasound endoscopy or enhanced CT/MRI scan.
6. At least one evaluable lesion in abdominal CT/MRI according to RESIST 1.1 is required.
7. Surgical consultation at enrolling site to confirm that patient will be able to undergo curative resection after completion of neoadjuvant therapy =< 56 days prior to registration.
8. Physical condition and adequate organ function to ensure the success of abdominal surgery.
9. Adequate hematological function: Neutrophil count ≥ 1.5 × 109/L, Platelets ≥ 100 × 109/L and Hemoglobin ≥90g/L.
10. Adequate liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN); AST (SGOT) and ALT (SGPT) < 2.5 × ULN in the absence of liver metastases, or < 5 × ULN in case of liver metastases. ALP ≤ 2.5 × upper limit of normal (ULN); ALB ≥30g/L.
11. Adequate renal function: Serum creatinine ≤ 1.5 x ULN, and creatinine clearance ≥ 60 ml/min.
12. Adequate coagulation function: INR/PT≤ 1.5 x ULN, aPTT≤ 1.5 x ULN.
13. No serious concomitant disease that will threaten the survival of patients to less than 5 years.
14. Male or female. Age ≥ 18 years and ≤80 years.
15. Written (signed) informed consent.
16. Good compliance with the study procedures, including lab and auxiliary examination and treatment.
17. Female patients should not be pregnant or breast feeding.
18. Female patients of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.

Exclusion Criteria:

1. Patients with distant metastasis or unresectable primary lesion.
2. Received prior treatment or receiving current treatment for this malignancy.
3. Patients who have digestive tract bleeding in 2 weeks before recruitment or with high risk of bleeding.
4. Perforation / fistula of GI tract in 6 months before recruitment.
5. Patients with upper GI tract obstruction or functional abnormality or malabsorption syndrome, which can affect absorption of apecitabine.
6. Patients with active autoimmune disease or history of refractory autoimmune disease.
7. Patients with active malignant tumor in recent 2 years, except the tumor studied in this research or cured locally tumor like resected basal cell or squamous cell skin cancer, superficial bladder cancer, cervical or breast carcinoma in situ.
8. Uncontrollable pleural effusion, pericardial effusion, or ascites in 2 weeks before recruitment.
9. Pulmonary disease history: interstitial pulmonary disease, non-infective pneumonitis, pulmonary fibrosis, acute pulmonary disease.
10. Uncontrollable systemic diseases, including diabetes, hypertension, etc.
11. Severe chronic or active infections in need of systemic antibacterial, antifungal, or antiviral treatment, including TB or HIV, etc.
12. Patients with untreated chronic hepatitis B or HBV DNA over 500 IU/ml or positive HCV RNA.

13. Patients with any cardiovascular risk factors below:

    1. cardiac chest pain occurring in 28 days before recruitment, defined as moderate pain that limits daily activity.
    2. pulmonary embolism with symptoms occurring in 28 days before recruitment.
    3. acute myocardial infarction occurring in 6 months before recruitment.
    4. any history of heart failure reaching grade 3/4 of NYHA in 6 months before recruitment.
    5. ventricular arrhythmias of Grade 2 or grater in 6 months before recruitment, or accompanied by supraventricular tachyarrhythmias requiring medical treatment.
    6. cerebrovascular accident within 6 months before recruitment.
14. Moderate or severe renal injury [creatinine clearance rate≤50 ml/min (according to Cockroft & Gault equation)], or Scr>ULN.
15. Dipyrimidine dehydrogenase (DPD) deficiency.
16. Allergic to any drug in this study.
17. History of allogeneic stem cell transplantation or organ transplantation.
18. Use of steroids (dosage>10mg/d prednisone) or other systemic immune suppressive therapy in 14 days before recruitment, except patients treated with regimens below: a. steroids for hormone replacement (dosage>10mg/d prednisone); b. steroids for local application with little systemic absorption; c. short -term (≤ 7 days) steroids for preventing allergy or vomiting.
19. Vaccinated with live vaccine in 4 weeks before recruitment.
20. Receiving immune (interleukin, interferon, thymin) treatment or treatment of other trials in 28 days before recruitment.
21. Receiving palliative radiation in 14 days before recruitment.
22. History of anti PD-1, PD-L1, PD-L2 or any other specific T cell co-stimulation or checkpoint pathway targeted treatment.
23. Patients who lose ≥20% of body weight within 2 months before enrollment.
24. For patients with uncontrolled epilepsy, CNS diseases or history of mental disorder, researchers should evaluate whether their diseases will impede their signing of informed consent or compliance of treatment.
25. Existing of potential situation which will impede drug administration or affect toxicity analysis or alcohol/ drug abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: neoadjuvant chemo-hypofractionated radiotherapy plus PD-1 antibody; Immunotherapy combined with chemotherapy (2 cycles): Intravenous tislelizumab (200mg, d1, q21d) in combination with XELOX regimen (capecitabine 1000 mg/m2 bid*14d + oxaliplatin 130mg/m2, d1, q21d);; Concurrent radiotherapy: Within one week after the first initiation of chemo-immunotherapy, concurrent hypofractionated radiotherapy will be started: intensity modulated radiotherapy was given for tumors, total dose:30Gy/12f, 2.5Gy/f.; D2 resection will be received three to five weeks after the completion of neoadjuvant therapy.

Combination product: neoadjuvant chemo-hypofractionated radiotherapy plus PD-1 antibody (Tislelizumab); Immunotherapy combined with chemotherapy (2 cycles): Intravenous tislelizumab (200mg, d1, q21d) in combination with XELOX regimen (capecitabine 1000 mg/m2 bid*14d + oxaliplatin 130mg/m2, d1, q21d);; Concurrent radiotherapy: Within one week after the first initiation of chemo-immunotherapy, concurrent hypofractionated radiotherapy will be started: intensity modulated radiotherapy was given for tumors, total dose:30Gy/12f, 2.5Gy/f.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pathological complete remission (pCR) rate	Pathologic complete response was defined as pT0N0M0	From date of treatment allocation and during treatment period up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiographic response	To assess radiographic response to neoadjuvant tislelizumab with concurrent chemoradiotherapy using RECIST 1.1.	From date of treatment allocation and during treatment period up to 3 months
The R0 resection rate	Complete Resection With no Tumor Within 1 mm of the Resection Margins (R0) Rate	Up to 3 years
Safety of neoadjuvant chemo-hypofractionated radiotherapy plus PD-1 antibody (Tislelizumab) Safety of neoadjuvant therapy	Adverse events (AE) of neoadjuvant therapy will be graded and documented according to NCI-CTCAE v5.0 from the beginning of treatment to 1 month after the last date of treatment.	1 month after the last date of treatment
Postoperative complications	Using the Clavien-Dindo classification	AEs of surgery refer to complications which happen during or in 30 days after operation.
Time to Relapse (TTR)	The median TTR and confidence interval will be estimated using the method of Kaplan-Meier	Time from the date of study registration to the date of 1st documented relapse/recurrence among patients who achieve R- resection, assessed up to 3 years
Progression-free Survival (PFS)	The distribution of PFS will be estimated using the method of Kaplan-Meier.	Time from the date of study registration to the date of death due to all causes, recurrences if R0 resections are achieved, progression disease before undergoing surgery, or R1/R2 resection at surgery, whichever comes first, assessed up to 3 years
Overall Survival (OS)	The distribution of OS will be estimated using the method of Kaplan-Meier.	Time from the date of study registration to the date of death due to all causes, assessed up to 3 years

Collaborators and Investigators

• Sponsor: Jiangsu Cancer Institute & Hospital
• Investigators: Principal Investigator: Cheng Chen, doctor, Jiangsu Cancer Institute & Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2023
• Primary Completion (Actual): March 15, 2025
• Study Completion (Actual): June 20, 2026

Study Registration Dates

• First Submitted: July 4, 2023
• First Submitted That Met QC Criteria: July 4, 2023
• First Posted (Actual): July 12, 2023

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 30, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: PD-1 Antibody; gastric or gastroesophageal junction adenocarcinoma; neoadjuvant chemo-hypofractionated radiotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Carcinoma; Esophageal Neoplasms; Adenocarcinoma; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; tislelizumab
• Other Study ID Numbers: jsCANCER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No